The long term objective of this project is to obtain a better understanding of the role of genetic and environmental factors in developmental neuropsychiatric disorders through the study of the specific disorder, Gilles de la Tourette's syndrome (TS). Research over the last decade has led to several notable advances in our understanding of TS and related conditions: 1) there is a greater range of phenotypic expression for TS including chronic tics and OCD); 2) TS and related disorders are much more common than had previously been thought; and 3) the syndrome appears to be transmitted as an autosomal dominant trait. Furthermore,the prevalence of TS and associated illnesses and their debilitating effects on those afflicted makes these conditions a major public health problem. Understanding the genetics of TS and associated behaviors will be of direct benefit to patients concerned about recurrence in their families; ultimately, clarifying the genetics of these conditions may elucidate their pathogenesis. Findings from our work suggest: 1) that TS is transmitted within families in a pattern consistent with autosomal dominant inheritance; 2) that there is an etiologic relationship between TS and OCD; 3) that family environment is associated with the expression of other associated behaviors; and 4) that specific environmental factors may be related to the severity of the illness. In this Project, we aim to examine specifically the role of genes and environment in the expression of TS and associated behaviors. We plan to conduct a prospective study of young unaffected children in families ascertained for linkage studies, enrolling approximately 60 additional children at risk to TS and associated conditions in these high density families. These data will make it possible to characterize more completely the nature of the relationship between TS and other traits. This study will also help to identify "non-genetic" factors important for the onset and variable expressions of TS and related disorders. Thus, data from this prospective study sample will help identify specific genetic and environmental factors associated with the variable expression of TS. In addition, all adults and adolescents in these families will be re-evaluated to update diagnostic information and to collect continuous measures of phenotypic data that will be incorporated into subsequent data analyses designed to delineate better the inherited phenotype in these families. Three types of information will be obtained from all family members: 1) diagnostic data collected via direct structured assessments; 2) neuropsychological data focusing on the domains of attention, inhibition, and compulsivity; and 3) measures of home environment and family functioning. These new data will be incorporated into phenotypic analyses designed to understand better the inherited TS phenotype as well as linkage analyses designed to examine hypotheses of genetic linkage of a hypothetical gene or genes for this phenotype to known polymorphic makers.